-
Tytuł:
-
Structure-based molecular hybridization design of Keap1-Nrf2 inhibitors as novel protective agents of acute lung injury.
-
Autorzy:
-
Zhang L; School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
Xu L; School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
Chen H; Department of Intervention, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
Zhang W; School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China.
Xing C; Department of Medicinal Chemistry, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA.
Qu Z; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: .
Yu J; School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China. Electronic address: .
Zhuang C; School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan, 750004, China; School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai, 200433, China. Electronic address: .
-
Źródło:
-
European journal of medicinal chemistry [Eur J Med Chem] 2021 Oct 15; Vol. 222, pp. 113599. Date of Electronic Publication: 2021 Jun 05.
-
Typ publikacji:
-
Journal Article
-
Język:
-
English
-
Imprint Name(s):
-
Publication: Paris : Editions Scientifiques Elsevier
Original Publication: Paris, S.E.C.T. [etc.]
-
MeSH Terms:
-
Acute Lung Injury/*drug therapy
Kelch-Like ECH-Associated Protein 1/*antagonists & inhibitors
NF-E2-Related Factor 2/*antagonists & inhibitors
Naphthalenes/*pharmacology
Protective Agents/*pharmacology
Sulfonamides/*pharmacology
Acute Lung Injury/metabolism ; Animals ; Dose-Response Relationship, Drug ; Drug Design ; Female ; Kelch-Like ECH-Associated Protein 1/metabolism ; Mice ; Mice, Inbred C57BL ; Molecular Structure ; NF-E2-Related Factor 2/metabolism ; Naphthalenes/chemical synthesis ; Naphthalenes/chemistry ; Protective Agents/chemical synthesis ; Protective Agents/chemistry ; Structure-Activity Relationship ; Sulfonamides/chemical synthesis ; Sulfonamides/chemistry
-
Contributed Indexing:
-
Keywords: Acute lung injury; Anti-inflammation; Keap1-Nrf2; Molecular hybridization; Naphthalensulfonamides; Protein-protein interaction
-
Substance Nomenclature:
-
0 (Keap1 protein, mouse)
0 (Kelch-Like ECH-Associated Protein 1)
0 (NF-E2-Related Factor 2)
0 (Naphthalenes)
0 (Nfe2l2 protein, mouse)
0 (Protective Agents)
0 (Sulfonamides)
-
Entry Date(s):
-
Date Created: 20210613 Date Completed: 20210901 Latest Revision: 20210901
-
Update Code:
-
20240105
-
DOI:
-
10.1016/j.ejmech.2021.113599
-
PMID:
-
34119834
-
Blocking the Kelch-like epichlorohydrin-related protein 1 (Keap1)-nuclear factor-erythroid 2 related factor 2 (Nrf2) pathway represents as a promising strategy to reduce oxidative stress and related-inflammation, including acute lung injury (ALI). NXPZ-2, a naphthalensulfonamide derivative, was previously reported to effectively inhibit the Keap1-Nrf2 protein-protein interaction (PPI) by our group. In the present work, a series of novel isothiocyanate-containing naphthalensulfonamides with the thioether, sulfoxide and sulfone moieties were designed by a structure-based molecular hybridization strategy using NXPZ-2 and the Nrf2 activator sulforaphane. They possessed good Keap1-Nrf2 PPI inhibitory activity and low cytotoxicity. The molecular docking study was performed to further explain the different activity of the thioether-, sulfoxide- and sulfone-containing naphthalensulfonamides. Among these new derivatives, 2-((N-(4-((N-(2-amino-2-oxoethyl)-4-((3-isothiocyanatopropyl)sulfinyl)phenyl)sulfonamido) naphthalen-1-yl)-4-methoxyphenyl)sulfonamido)acetamide (SCN-16) showed a good K D2 value of 0.455 μM to disrupt the PPI. In an LPS-induced peritoneal macrophage cell model, this compound could cause a significant increase in the nuclear Nrf2 protein, decrease in the cytosolic Nrf2 protein, and further elevate the downstream protective enzymes HO-1 and NQO-1, which were better than the lead compound NXPZ-2 and sulforaphane. What's more, the production of ROS and NO and the expression of pro-inflammatory cytokine TNF-α were also suppressed. In the LPS-induced ALI model, SCN-16 could significantly reduce LPS-induced inflammations and alleviate lung injuries by triggering Nrf2 nuclear translocation. Collectively, our results suggested that SCN-16 could be a novel lead compound targeting Keap1-Nrf2 protective pathway for clinical treatment of ALI.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
